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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P9/06—Antiarrhythmics
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
  • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
  • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
  • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
  • C07C2603/20—Acenaphthenes; Hydrogenated acenaphthenes
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
  • C07C2603/28—Phenalenes; Hydrogenated phenalenes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings

Definitions

• the present invention relates to new tricyclic derivatives, their preparation process and the pharmaceutical compositions containing them.
• the ligands of the melatoninergic system have interesting properties pharmacological on the central nervous system, in particular anxiolytics and antipsychotics (Neuropharmacology of Pineal Sécrétions, 1990, 8 (3-4), pp 264-272) and analgesics (Pharmacopsychiat., 1987, 20, pp 222-223) as well as for treatment of Parkinson's diseases (J. Neurosurg. 1985, 63, pp 321-341) and Alzheimer's (Brain Research, 1990, 528, pp 170-174).
• the compounds of the present invention are new and have a very high affinity for melatonin receptors and / or a selectivity for one or the other of the melatoninergic receptor subtypes.
• the present invention relates more particularly to the compounds of formula (I)
• A forms with the group to which it is linked a tricyclic system chosen from Ai, A 2 , A 3 or t :
• R 1 represents a hydrogen atom, a halogen atom, a linear or branched alkyl group (CC 6 ), linear or branched alkoxy (C ⁇ -C 6 ), hydroxy, or oxo,
• R 2 and R 3 identical or different, represent a halogen atom, a group Ra, OR a , COR a , OCOR, or COORa (with R, representing a hydrogen atom, an alkyl group (Ci- Ce) linear or branched optionally substituted, trihaloalkyl (C I -C ⁇ ) linear or branched, an alkenyl group (C 2 -C 6 ) linear or branched optionally substituted, an alkynyl group (C 2 -C 6 ) linear or branched optionally substituted , a cycloalkyl group (C 3 -C 8 ) optionally substituted, a cycloalkyl group (C 3 -C 8 ) alkyl (Ci-Ce) linear or branched optionally substituted, or an aryl group optionally substituted),
• R representing a hydrogen atom, an alkyl group (Ci- Ce) linear or branched optionally substituted, trihaloalky
• R 2 ) m and (R 3 ) m signifies that the cycle concerned can be substituted by 1 to 3 groups (identical or different) belonging to the definitions of R 2 and R 3
• n is an integer such that 0 ⁇ n ⁇ 3
• Z represents an oxygen atom or a sulfur atom
• R 5 represents a group R a or a group NR 6 R 7 in which R 6 and R 7 , identical or different, represent a group R ,
• the compound of formula (I) cannot represent N- (4-methyl-2,3-dihydro-JH-1- phenalenyl) -1-cyclopropanecarboxamide, N- (4-methyl-2,3-dihydro- / Hl- phenalenyl) -2-chloroacetamide, 2-methyl-1,3,4,5-tetrahydrobenzo [c- /
• aryl means a phenyl or naphthyl group optionally substituted by one or more groups, identical or different, chosen from hydroxy, alkoxy (CC 6 ) linear or branched, alkyl (C ⁇ -C 6 ) linear or branched, cyano, nitro, amino, trihaloalkyl, or halogen atoms,
• cycloalkyle alkyl means that the cyclic part is substituted by one or more groups, identical or different, chosen from hydroxy, linear or branched (C1-C6) alkoxy, oxo, or halogen atoms,
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, camphoric acids. , oxalic, etc.
• R 1 represents a hydrogen atom, a halogen atom, an alkyl group (C ⁇ -C 6 ) linear or branched, alkoxy (C ⁇ -C 6 ) linear or branched, hydroxy, or oxo,
• R 2 and R 3 identical or different, represent a halogen atom, a group R " , OR ,, CORa, OCORa or COORa (with R, representing a hydrogen atom, an alkyl group (Ci-Cé ) linear or branched optionally substituted, trihaloalkyl
• Z represents an oxygen atom or a sulfur atom
• R 5 represents a group R, or a group NR 6 R in which R 6 and R 7 , which are identical or different, represent a group Ra, - or a group C - NR R in which Z, R 6 and R 7 are as defined
• alkyl alkenyl
• alkynyl alkynyl
• cycloalkyle and “cycloalkyle alkyl” means that the cyclic part is substituted by one or more groups, identical or different, chosen from hydroxy, linear or branched (Ci -Ce) alkoxy, oxo , or halogen atoms,
• A forms with the group to which it is linked a tricyclic system chosen from A " ⁇ ,
• R 1 represents a hydrogen atom, a halogen atom, an alkyl group (C ⁇ -C 6 ) linear or branched, alkoxy (C ⁇ -C 6 ) linear or branched, hydroxy, or oxo,
• R 2 and R 3 identical or different, represent a halogen atom, a group R a , OR a , COR a , OCORa or COOR a (with R, representing a hydrogen atom, an alkyl group (C ⁇ -C 6 ) linear or branched optionally substituted, trihaloalkyl
• n is an integer such that 0 ⁇ n ⁇ 3
• Z represents an oxygen atom or a sulfur atom
• R 3 represents an R * group or an NR R group in which R 6 and R 7 , which are identical or different, represent an R group "
• connection can be single or double, it being understood that the valence of the atoms is respected
• aryl means a phenyl or naphthyl group optionally substituted by one or more groups, identical or different, chosen from hydroxy, alkoxy (C ⁇ -C 6 ) linear or branched, (Ci-Ce) linear or branched alkyl, cyano , nitro, amino, trihaloalkyl, or halogen atoms,
• alkyl alkenyl
• alkynyl alkynyl
• groups are substituted by one or more groups, identical or different, chosen from hydroxy, linear or branched alkoxy (Ci-Ce) , aryl, or halogen atoms
• cycloalkyle and “cycloalkyle alkyl” means that the cyclic part is substituted by one or more groups, identical or different, chosen from hydroxy, linear or branched (Ci -Ce) alkoxy, oxo , or halogen atoms,
• the preferred compounds of the invention are those for which A forms with the groups to which it is linked a tricyclic system of formula Ai.
• the preferred values of n are 0, 1 or 2.
• the preferred values of p are 0, 1 or 2.
• the preferred substituents R 2 and R 3 of the invention are the hydrogen atom, the alkoxy or alkyl groups.
• the preferred group R 1 of the invention is the hydrogen atom.
• the invention relates to compounds substituted by the chain in position a or c and more particularly those for which p represents an integer equal to 0 (and in this case the connection is simple), 1 or 2.
• the preferred groups B of the invention are the group NHCOR 5 in which R 5 is as defined above (such as for example the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl groups), or the group CONHR 6 in which R 6 is as defined above (such as, for example, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl groups).
• the invention relates to tricyclic systems 2,3-dihydrophenalene, 1,2-dihydroacenaphthylene or 7,8,9,10-tetrahydrocyclohepta [- / e] naphthalene, substituted or not on the naphthalene part by one or several alkoxy or alkyl groups, and substituted at a or c by a group " X in which B represents a group
• B represents a group NHCOR 5 or CONHR 6 in which R 5 and R 6 represent an alkyl, alkenyl, alkynyl, trihaloalkyl, cycloalkyl, cycloalkylalkyl, aryl group or arylalkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, propargy
• B represents an NHCOR 5 or CONHR 6 group in which R 5 and R 6 represent an alkyl, alkenyl, alkynyl, trihaloalkyl group, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl such as for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, vinyl, propargyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
• the invention relates to N - [(4-Methoxy-2,3-dihydro- / Hl-phenalenyl) methyl] acetamide, N - [(4-Methoxy-2,3-dihydro- / H- phenalenyl) methyl] propionamide, N - [(4-Methoxy-2,3-dihydro- / Hl-phenalenyl) methyl] -cyclopropane carboxamide, N - [(4-Methoxy-2,3-dihydro- / Hl- phenalenyl) methyl] butanamide, N- [2- (4-Methoxy-2,3-dihydro- / Hl-phenalenyl) ethyl] acetamide, N- [2- (4-Methoxy-2,3-dihydro-7H -l-phenalenyl) ethyl] propanamide, N- [2- (4-Methoxy-2,3-
• the invention also extends to the process for the preparation of the compounds of formula (I) in which A forms with the groups to which it is linked a tricyclic system of formula (Ai) characterized in that one uses as starting material:
• Y represents a group (CH 2 ) q (where q is 1, 2 or 3, or q is 0 when the representation is a single bond),
• Y 1 represents a group (CH 2 ) q (where q 'is 0, 1, 2 or 3), substituted by a group
• Y 3 represents a group (CH 2 ) q " (where q" is 0, 1, 2 or 3), substituted by a group R 1 as defined above with q '+ q " ⁇ 3 and R 1 necessarily represents a hydrogen atom in at least one of the two groups Y 1 and Y 3 ,
• Hal represents a halogen atom and R 1 , R 2 , R 3 , n, p, X, m, m 'and the representation are defined in the same way as above,
• the compounds (I / a) to (1/1) which can be purified according to a conventional separation technique, which, if desired, are converted into their addition salts with a pharmaceutically acceptable acid or base, and of which the isomers are optionally separated according to a conventional separation technique.
• the invention also relates to the process for the preparation of the compounds of formula (I) in which A forms with the groups to which it is linked a tricyclic system of formula (A 2 ), (A 3 ) or (A t ) characterized in that we use as starting material: * the compound of formula (XI)
• R, R, Y, m and the representation are defined as above, and
• Y ' represents a group (CH 2 ) q ' substituted by a group R 1 where q 'and R 1 are as defined above,
• Y ' represents a group (CH 2 ) q - substituted by a group R 1 where q "and R 1 are as defined above, with 0 ⁇ (q' + q") ⁇ 4, and R 1 necessarily represents an atom d 'hydrogen in at least one of the two groups Y' 1 and Y ' " ⁇ and D forms, with the benzene nucleus one of the three structures (A 2a ), (A 5a ) or (Au):
• R 2 , RX, m and m ' are as defined above and T and T', different, represent a hydrogen atom or a group -CHO
• T 4 and T' 4 represent a hydrogen atom or form, with the atom of
• R 2 , R 3 , X, G, m, m 'and the representation are defined as above, and T's and T 5 , different, represent a hydrogen atom or a COOH group,
• T' é and Te represent a hydrogen atom or form, with the carbon atom which carries them a group where p is defined as above, it being understood that one of the two groups T ' 6 or T 6 represents a hydrogen atom,
• T' 7 and T 7 represent a hydrogen atom or form, with the carbon atom which carries them a group in which p, R 6 and R 7 are defined as above, it being understood that one of the two groups T ' 7 or T7 represents a hydrogen atom,
• T' 8 and T 8 represent a hydrogen atom or form, with the carbon atom which carries them a group in which p, R 6 and R 7 are. defined as above, it being understood that one of the two groups T 8 or T ' 8 represents a hydrogen atom,
• T' 9 and T 9 represent a hydrogen atom or form, with the carbon atom which carries them a group y ⁇ X> ⁇ NH 2 or p is as defined above, it being understood that one of the two groups T 9 or T ' 9 represents a hydrogen atom,
• T'io and Tio represent a hydrogen atom or form, with the carbon atom which carries them a group ' ::: ⁇ r7 P ⁇ -NHCOR in which p and R 5 are defined as above, it being understood that one of the two groups T' ] 0 or Tio represents a hydrogen atom,
• T'n and Tu represent a hydrogen atom or form, with the carbon atom which carries them a grouping CZR 5 where P, R a , 5 and Z are defined as above, it being understood that one of the two groups T'n or Tn represents a hydrogen atom,
• the compounds (I / m) to (I / v) can also be obtained according to a similar process characterized in that a compound of formula (XXIV) is used as starting material: in which R 2 , D and m are as defined above.
• the starting compounds are:
• the compounds of the invention and the pharmaceutical compositions containing them prove to be useful for the treatment of disorders of the melatoninergic system.
• the pharmacological study of the derivatives of the invention has indeed shown that they are non-toxic, endowed with a very high selective affinity for melatonin receptors and possess important activities on the central nervous system and, in particular, therapeutic properties have been noted on sleep disorders, anxiolytic, antipsychotic and analgesic properties as well as on microcirculation which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depressions, cardiovascular pathologies, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia , psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal aging l or pathological, migraine, memory loss, Alzheimer's disease, as well as in disorders of the cerebral circulation.
• the products of the invention have properties of ovulation inhibitors, immunomodulators and that they are capable of being used in the treatment of cancers.
• the compounds will preferably be used in the treatment of seasonal depressions, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
• the compounds will be used in the treatment of seasonal depressions and sleep disorders.
• the present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
• compositions according to the invention there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per. or transcutaneous, rectal, perlingual, ocular or respiratory and in particular the simple or coated tablets, the sublingual tablets, the sachets, the packets, the capsules, the glossettes, the tablets, the suppositories, the creams, the ointments, the dermal gels, and oral or injectable ampoules.
• the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.01 mg and 1 g per 24 hours in 1 or more takes.
• the organic phase is treated with an IN hydrochloric acid solution (190 ml), then with a saturated NaHCO 3 solution (125 ml) and with a saturated NaCl solution (125 ml). After drying over MgSO 4 and evaporation under reduced pressure, the oil obtained is recrystallized from cyclohexane. Melting point: 86 ° C Elemental microanalvse:
• stage C The decarboxylation of the diacid obtained in stage C (8.1 g, 2.95.10 " 2 mol) is carried out in a 100 ml monocol purged with argon heated by a metal bath at 165- 178 ° C until the end gas evolution
• the acid is recrystallized from a CH 2 C1 2 / petroleum ether mixture.
• Stage F 2- (4-Methoxy-2,3-dihydro- / H-1-phenalenyliden) ethyl acetate
• triethylamine (645 ⁇ l, 4.63 mmol, 1.15 eq.) Is added dropwise to a solution cooled to 0 ° C of the acid obtained in stage ⁇ (1.03 g , 4.02 mmol) in a mixture of acetone (17 ml) and water (1 ml).
• the ethyl chloroformate (500 ⁇ l, 5.23 mmol, 1.30 eq.) Is then added slowly at 0 ° C; a gas evolution is visible.
• the medium is stirred at 0 ° C for 30 minutes; after observation of the disappearance of the starting product on TLC (C ⁇ 2CI2), a solution of sodium azide (350 mg, 5.23 mmol, 1.30 eq.) in water (1.7 ml) is added at 0 ° C. The medium is maintained at this temperature for one hour.
• a TLC (CH2CI2) indicates the formation of the azide.
• the medium is poured onto an ice / water mixture and then extracted with ether. The ethereal phases are washed with water and then dried over Na2SO 4 , and evaporated under vacuum without heating.
• the azide taken up in 10 ml of anhydrous toluene is heated to 80 ° C. until there is no more evolution of nitrogen.
• the oil corresponding to the isocyanate is heated to 100 ° C. with a 20% hydrochloric acid solution (8 ml) for 3 hours; the medium is stirred overnight at room temperature.
• the reaction medium is diluted in water, filtered through filter paper, and extracted with ether.
• the combined ethereal phases are washed with water and dried over K2CO 3 .
• the amine is converted to the hydrochloride after solubilization in ether and treatment with a 4N hydrochloric ether solution. Melting point: 237 ° C Elemental microanalvse:
• the catalyst is prepared from 55 mg of PdCl 2 in 5 ml of methanol treated with
• the procedure is as in Stage F of Preparation 1, replacing the triethylphosphonoacetate with the triethylphosphonopropanoate.
• Stages B, C and D are identical to stages G, ⁇ and I of Preparation 1.
• Preparation 33 is obtained by proceeding as in Preparation 32 from the ketone obtained in Preparation 3.
• Stage A 4- (4-Methoxy-2,3-dihydro- / Hl-phenalenyl) nitrobutane
• the ketone obtained in stage E of Preparation 1 is subjected to the conditions of stages A and B of Preparation 19 by replacing the diethylcyanomethylphosphonate by the diethylcyanopropylphosphonate.
• stage A The nitrile obtained in stage A is hydrolyzed under the conditions of the
• stage A The compound obtained in stage A is reduced under the conditions of stage G of Preparation 1.
• Stage C 4- (2,7-Dimethoxy-1-naphthyl) -butanoic acid
• the ester obtained in stage B is saponified under the conditions of stage H of Preparation 1.
• Preparation 40 (5-methoxy-6,7,8,9-tetrahydro-2-oxobenzo [crf] azulen-9-yl) methylamine The procedure is as in Preparation 38 starting from 5-methoxybenzo [ô] furan-4-carbaldehyde.
• the nitrile obtained in Preparation 63 (500 mg, 2.1 1.10 "3 mol) is heated to reflux in the presence of 30% sodium hydroxide (8 ml), methanol (8 ml) and d ethanol (8 ml) for 48 hours After cooling, the medium is poured into an ice / water mixture The medium is acidified with hydrochloric acid and extracted three times with ethyl acetate and once with dichloromethane The organic phases are washed separately with water and with a saturated NaCl solution, dried over MgSO 4 and then evaporated under reduced pressure The title acid is obtained in the form of a pale yellow solid.
• stage A acid (515 mg, 2.01.10 “3 mol) -in a mixture of acetone (20 ml) and water (600 ⁇ l), triethylamine (322 ⁇ l, 2.31.10 “3 mol, 1.15 eq.) and ethyl chloroformate (250 ⁇ l, 2.61.10 '3 mol, 1.30 eq.).
• Acyl azide is formed by the action of a solution of sodium azide (175 mg, 2.61.10 "3 mol, 1.30 eq.) In water (1 ml). After heating in anhydrous toluene ( 5 ml), the isocyanate is hydrolyzed with a 20% hydrochloric acid solution (6 ml).
• the medium is stirred overnight at room temperature.
• the reaction medium is diluted in water, filtered through filter paper, and extracted with ether.
• the combined ethereal phases are washed with water and dried over K 2 CO 3 . evaporation of the solvent under reduced pressure, the amine is converted to the hydrochloride after solubilization in ether and treatment with a 4N hydrochloric ether solution After drying, the title product is obtained in the form of a white solid.
• the aluminum chloride (11.2 g, 8.38 ⁇ 10 ⁇ 2 mol, 2.6 eq.) Is gradually added to the spatula.
• the solution is stirred for twenty minutes and becomes green-black in color.
• the medium is poured into an ice / HCl IN mixture.
• the combined organic phases are washed with water, then treated with a saturated NaHCO 3 solution and finally washed with a saturated NaCl solution. After drying over MgSO and evaporation under reduced pressure, the title product is obtained in the form of a yellow solid. Melting point: 123 ° C
• triethylamine (3.49 ml, mol, 1.15 eq.) is added dropwise to a solution cooled to 0 ° C of the acid obtained in stage D (4.62 g, 2.18.10 " mol) in a mixture of acetone (95 ml ) and water (5.4 ml).
• Ethyl chloroformate (2.71 ml, 2.83.10 "2 mol, 1.30 eq.) is then added slowly at 0 ° C; a gas evolution is visible.
• the medium is stirred at 0 ° C for 30 minutes; after observation of the disappearance of the starting product on TLC (CH 2 C1 2 ), a solution of sodium azide (1.89 g, 2.83.10 "2 mol, 1.30 eq.) in water ( 9.2 ml) is added at 0 ° C. The medium is maintained at this temperature for one hour. The medium is poured onto an ice / water mixture then extracted with ether. The ethereal phases are washed with water and then dried over Na 2 SO, and evaporated in vacuo without heating, the acyl azide taken up in 50 ml of anhydrous toluene is heated to 80 ° C. until there is no more evolution of nitrogen.
• the catalyst is prepared from 55 mg of PdCl 2 in 5 ml of methanol treated with 25 mg of sodium borohydride. After 15 minutes of stirring, the derivative obtained in stage A
• stage B The nitrile obtained in stage B (900 mg, 4.66 ⁇ 10 ⁇ 3 mol) diluted in methanol (30 ml) is hydrogenated with vigorous stirring at room temperature, in the presence of ammonia (2 ml) and Raney nickel. After 23 hours, the starting product has disappeared After filtration through Celite, then rinsing and evaporation under reduced pressure of the solvent, the title amine is obtained in the form of an oil, which is used without purification.
• the reaction medium is stirred overnight at room temperature, then diluted in water, filtered through celite and after adding a few drops of sodium hydroxide, extracted twice with ether.
• the basic aqueous phase is acidified with cold HCl.
• the desired acid is extracted with ether.
• the solid residue is chromatographed on a column of silica gel (1. CH 2 C1 2 ; 2. CH 2 C1 2 / MeOH: 97/3). A white solid corresponding to the mixture of the two E / Z isomers of the title compound is obtained.
• stage A The derivative obtained in stage A (3.4 g, 1.40 ⁇ 10 ⁇ 2 mol) is dissolved in ethyl acetate (90 ml) in the presence of 5% palladium on carbon.
• the medium is purged with argon and placed under a hydrogen atmosphere After 15 hours of hydrogenation, the reaction medium is filtered through celite, rinsed, then evaporated under reduced pressure.
• the title product is isolated in the form of white crystals Melting point: 88 ° VS Elementary microanalysis:
• the hydrochloride obtained in Preparation 1 (382 mg, 1.45.10 -3 mol) is taken up with dichloromethane and treated with ammonia until the solid is dissolved and a basic pH is obtained for the aqueous phase. After separation of the phases, the amine is dried over K2CO3. At 0 ° C, the amine (320 mg, 1.41.10 " 3 mol) is taken up in anhydrous dichloromethane (10 ml) in the presence of triethylamine on potassium hydroxide (295 ⁇ l, 2, 12.10 -3 mol, 1.5 eq Cyclopropionyl chloride (130 ⁇ l, 1.43 ⁇ 10 3 mol, 1 eq.) Is added dropwise at 0 ° C.
• Example 3 The compound obtained in Example 3 is subjected to demethylation in the presence of a conventional agent such as BBr 3 for example.
• Example 6 The compound obtained in Example 6 is reacted in a basic system in the presence of benzyl chloride.
• the compound of Preparation 1 is suspended in pyridine then the cyclobutyl isocyanate is added dropwise, and the reaction medium is heated. When the reaction is complete, the reaction medium is poured onto ice water and acidified with a solution of IN hydrochloric acid. After conventional treatment, the title compound is isolated pure.
• Example 23 The compound obtained in Example 23 is conventionally treated with the Lawesson reagent.
• Example 26 The compound obtained in Example 26 in solution in tetrahydrofuran is added dropwise at 0 ° C to a suspension of NaH (2.2 eq) in THF. Dimethyl sulfate (2.3 eq) is added very slowly at 0 ° C then the reaction medium is stirred at ambient temperature. When the reaction is complete, a conventional treatment is carried out and the title product is isolated by chromatography.
• Example 27 The compound of Example 27 in solution in dichloromethane is added dropwise at 0 ° C to a suspension of aluminum chloride and benzylthiol. The reaction is followed by TLC. When it is finished, the reaction medium is thrown on ice and then acidified with IN HCl. A standard extraction is then carried out and the title compound is isolated by chromatography.
• Example 7 The procedure is as in Example 7, starting from the compound obtained in Example 28, replacing the benzyl chloride with 3-chloro-1-propyne.
• the nitrile obtained in stage A of Preparation 19 (500 mg, 2.1 1.10- 3 mol) in tetrahydrofuran (25 ml) is hydrogenated at room temperature in the presence of propionic anhydride (500 ⁇ l, 3.90.10- 3 mol, 1.85 eq.) and Raney nickel. After 30 hours of hydrogenation, the reaction medium is filtered through celite, rinsed and evaporated under reduced pressure. The residue is then taken up in dichloromethane and washed with water, then with a saturated solution of NaHCO 3 , then with water. After drying over MgS ⁇ 4 and evaporation of the solvent, the mass residue 650 mg is purified by flash chromatography (CH 2 C1 2 / methanol: 99/1).
• the title compound is obtained by subjecting the compound of Example 39 to the Lawesson reagent.
• Example 5 The procedure is as in Example 5 starting from the compound of Example 38, replacing the methyl sulfate with butyl iodide.
• Example 48 The procedure is as in Example 48, starting from the compound of Example 50, replacing the butyl iodide with Hexyl iodide.
• the title product is obtained by condensation of N-cyclobutylamine on the acid obtained in Preparation 27 after transformation into acid chloride.
• Example 64 The procedure is as in Example 64, starting from the compound obtained in Example 66.
• EXAMPLE 70 N-.2-.1.6-Di ⁇ -ethoxv-7.8.9.10-tétrahvdrocvcIoheptal.7e.naphtalen-7- yl) ethyljacetamide
• Example 66 The procedure is as in Example 66 by condensing the N-Pentylamine on the acid chloride of the compound obtained in Preparation 52.
• Example 7 The procedure is as in Example 7, starting from the compound obtained in Example 89.
• Example 8 The procedure is as in Example 8 starting from the compound obtained in Example 89.
• Example 24 The procedure is as in Example 24, starting from the compound obtained in Example 87.
• Example 5 The procedure is as in Example 5 starting from the compound obtained in Example 96.
• the compounds of Examples 104 and 105 are obtained by the action of HBr on the compound obtained in Example 84.
• the title compound is obtained by conventional oxidation of the alcohol obtained in Example 104.
• the reaction medium is stirred at room temperature for 40 minutes. After separation of the phases, washing of the organic phase with a saturated NaHCO 3 solution, water, then a saturated NaCl solution and drying over MgSO 4 , and finally evaporation of the solvent under reduced pressure, the residue is purified by flash chromatography (1 CH 2 C1 2 ; 2. CH 2 C1 2 / MeOH: 99/1). After recrystallization from a hexane / AcOEt mixture, the title compound is obtained in the form of a white solid. Melting point: 100 ° C Elemental microanalysis: CHN% calculated 76.74 7.80 4.71
• Example 108 The procedure is as in Example 108, replacing acetic anhydride with butyric anhydride.
• the title product is isolated in the form of an oil.
• Example 1 1 The procedure is as in Example 1 1 1, replacing the propionic anhydride with acetic anhydride.
• the title product is isolated in the form of a white solid. Melting point: 125 ° C
• Example 117 The procedure is as in Example 117, replacing acetic anhydride with propanoyl chloride.
• the title product is isolated in the form of a white solid.
• Example 121 The procedure is as in Example 121, starting from the acid obtained in Preparation 67. Melting point: 175 ° C.
• Example 123 The procedure is as in Example 123, replacing acetic anhydride with cyclopropanoyl chloride.
• Example 131 The procedure is as in Example 131 starting from the nitrile obtained in stage A of Preparation 71.
• the title product is isolated in the form of a white solid.
• Acute toxicity was assessed after oral administration in groups of 8 mice (26 ⁇ 2 grams). The animals were observed at regular intervals during the first day and daily during the two weeks following the treatment. The
• the melatonin receptor binding studies of the compounds of the invention were carried out according to conventional techniques on the cells of the sheep pars tuberalis.
• the pars tuberalis of the adenohypophysis is indeed characterized, in mammals, by a high density of melatonin receptors (Journal of Neuroendocrinology, I, pp 1-4, 1989).
• the IC 50 values found for the compounds of the invention show that the binding of the compounds tested is very strong for one or the other of the subtypes of mti or MT 2 receptors, these values being situated in a 0.1 to 1 OnM interval
• the products of the invention are administered by the esophageal route to batches of ten mice.
• One batch receives gum syrup.
• the animals are placed in compartments, the floor of which comprises four metal plates. Each time the animal passes from one plate to another, it receives a slight electric shock (0.35 mA). The number of passes is recorded for one minute.
• the compounds of the invention significantly increase the number of passages, which shows the anxiolytic activity of the derivatives of the invention.
• the effects of the molecules are tested on many parameters and, in particular, on the circadian rhythms of locomotor activity which represent a reliable marker of the activity of the endogenous circadian clock.
• the rats receive a daily administration of the test molecule.
• test substance is administered intraperitoneally to a group of 3 mice 30 min before exposure to anesthesia with chloroform. The animals are then observed for 15 min. The absence of recording of arrhythmias and heart rates greater than 200 beats / min (control 400-480 beats / min) in at least two animals indicates significant protection

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